Evaluation of a cancer pain model for the testing of long‐acting analgesics. The effect of ms contin in a double‐blind, randomized crossover design

Abstract

A double-blind, double-dummy, crossover study compared oral controlled-release morphine sulfate (MS Contin tablets [MSC], Purdue Frederick, Norwalk, CT) every 12 hours, and immediate-release morphine sulfate (IRMS) tablets, every 4 hours, in 14 evaluable patients with chronic cancer pain. The test model described showed assay sensitivity for steady-state analgesia, requiring relatively few subjects to yield statistical significance in pharmacologic potency estimates. Initial doses were the calculated equivalents of about one third the previous opioid requirements or at least 30 mg MSC every 12 hours or 15 mg IRMS every 4 hours. This was generally subtherapeutic; hence, additional IRMS was available for break-through pain. Doses of MSC and IRMS were titrated upwards until the requirement for rescue IRMS was less than 20% of the total daily amount of morphine. In both study phases, the total dose of morphine increased significantly from the first day to the last, on which it was significantly (34%) higher for IRMS than MSC. Pain was significantly less intense and frequent in the last 24 hours of each treatment arm than in the first, and equally well controlled by both regimens. The two treatments were equipotent in a pharmacologic assay using dosages and pain scores. The requirement for rescue analgesia was similarly comparable for both treatments, decreasing significantly with upward dose titration. The few side effects experienced (one with MSC and three with IRMS) did not include serious reactions such as respiratory depression. It is concluded that MSC, 12-hourly, controls cancer pain as effectively and safely as IRMS on a 4-hour schedule. MS Contin exhibits a 12-hour duration of action as previously shown in other well-controlled trials. A problem of pain exacerbation at the start of each study phase was found to be associated with the design of this study. It may be resolved with a higher initial study dose and/or use of a patient-controlled analgesia device for parenteral rescue doses.

The Adverse Effects of Morphine: A Prospective Survey of Common Symptoms During Repeated Dosing for Chronic Cancer Pain

“…8 Some symptoms were more common (but not statistically significant) with liquid morphine (anorexia, dry mouth, flushing, and urinary hesitancy) in our study; unfortunately, these specific symptoms were not evaluated as potential side effects in any prior studies. 16,17,27,28 This pilot study used a previously unevaluated tool with a patient interview technique. The tool closely resembles the traditional symptom review used in routine daily clinical practice.…”

“…A conflicting issue is that the general symptoms in cancer patients with advanced disease (when opioids are frequently prescribed) are also only partially documented. [14][15][16] Although a few prospective studies of individual opioid-related symptoms such as dry mouth 17 and myoclonus 18 have appeared recently, there has been no prospective evaluation of the possible known side effects of morphine during longterm use in cancer patients. We will report the results of a naturalistic 4-week observational study of clinical practice in 30 consecutive patients given morphine in repeated, regular dosing for chronic severe pain due to advanced cancer.…”

Controlled clinical trials in cancer pain. How controlled should they be? A qualitative systematic review

“…The criteria differed for each of these trials and for adequate pain relief included: 'maximum 3 on a 7 point VRS, and not more than two daily requests for rescue analgesia' (Klepstad et al, 2003); 'no need for dose adjustment for three or more days and no morphine sulphate solution intake exceeding 50% of the daily morphine dosage supplied by the test drug' (Deschamps et al, 1992); 'no more than three supplementary doses of immediate release morphine per day' (Portenoy et al, 1989); 'required daily rescue doses over 2 days interval not more than 20% of the total daily morphine doses' (Cundiff et al, 1989); 'over a 48-h period, the q12h dose was unchanged, less than two supplemental analgesic doses were taken per day, the dosing regimen for any non-opioids or adjuvants was unchanged, and the patient reported that pain control was acceptable and any side effects were tolerable' (Mucci-LoRusso et al, 1998). Inadequate pain relief was defined as: 'more than two doses of rescue medication/24 h, or moderately severe global pain score' (Stambaugh et al, 2001); 'despite dose escalation, pain intensity rating more than three on a five point VRS' (Wilder- Smith et al, 1994).…”

Controlled-release morphine tablets in patients with chronic cancer pain

“…Individual studies showed no difference between CR morphine tablets and IR morphine or other comparators in terms of the therapeutic profile. For example, Cundiff et al 17 showed that CR morphine and IR morphine were equipotent pharmacologically in a parallel-line log ratio assay using dosages and pain scores. The potency of CR morphine relative to IR morphine was 1.08 for pain intensity and 1.03 for pain frequency with 95% confidence limits of 0.93-1.25 and 0.74 -1.3, respectively.…”